Reliable changes in EEG sleep characterize depression although the neurobiology of these changes remain unknown. Preliminary findings from our lab suggest that depressed patients suffer from two related behavioral state changes: deficits in the generation and maintenance of slow wave sleep, and increases in measures related to behavioral arousal including sleep continuity and REM sleep disturbances. We propose that these changes are related to functional alterations in two related brain systems: 1) an anterior paralimbic and prefrontal cortex system (anterior cingulate, basal forebrain, hypothalamus and prefrontal cortex); and 2) a generalized arousal system (pontine reticular formation, thalamus and amygdala). Career development activities to further this line of investigation focus on three areas: 1) the application o neurobiological studies to longitudinal clinical trials; 2) the cognitive neuroscience of limbic/prefrontal cortex interactions and their applications to the functional neuroanatomy of sleep in depression; and 3) the pharmacologic modulation of limbic/prefrontal cortex interactions across behavioral states in depression. The research plan of the K24 award will test a functional neuroanatomic model of behavioral state (sleep/wake) changes in depression that are proposed to be central to the pathophysiology of depression. We will recruit 27 depressed outpatients and 27 healthy controls into a five-day sleep brain imaging study. Measures of behavioral state include EEG sleep and regional quantitative EEG. Measures of brain function include -FDG PET relative regional glucose metabolism during waking, NREM and REM sleep. Repeated measures multivariate analyses of covariance and multivariate multiple regressions will test the above hypotheses. This plan has previously been funded as the R01 "Sleep-guided PET studies in depression" (EA Nofzinger, P1, MH61 566). Findings from this study are expected to significantly advance our understanding of the pathophysiology of depression. The goals of mentoring activities are to recruit and mentor at least one new trainee per year from the ranks of medical students, residents, or post-doctoral fellows. Success in mentoring will be measured by trainee's productivity in peer-reviewed publications, presentations of research at scientific meetings, and pursuit of independent career development awards and funding proposals. The principal investigator will mentor trainees in conducting patient* oriented research, including the development of IRB approved protocols, implementing a research plan, and interpreting and presenting data. Content areas for mentoring young investigators include functional neuroimaging methods for use during sleep, the neuroscience of behavioral state regulation, and in the ethical conduct of research.